2-[[[2-[(hydroxyacetyl)amino]-4-pyridinyl]methyl]thio]-N-[4-(trifluoromethoxy)phenyl]-3-pyridinecarboxamide benzenesulfonate, crystal of same, crystal polymorph thereof, and methods for production thereof

ABSTRACT

In the course of developing 2-[[[2-[(hydroxyacetyl) amino]-4-pyridinyl]methyl]thio]-N-[4-(trifluoromethoxy) phenyl]-3-pyridinecarboxamide(compound A), there are the multiple problems: 1) compound A or its salt is difficult to be recrystallized, the storage stability largely differs depending on the kind of the salt, and it is very difficult to obtain a salt of compound A having excellent storage stability; 2) in a crystallization process of compound A, it is very difficult to control a crystal polymorph, and 3) compound A (free body) causes mineral deposition in the stomach when it is orally administered repeatedly. For solving these problems, we made examination focusing on the kind of the salt and, as a result, found that 1) benzenesulfonate of compound A does not decompose by light, humidity and other factors in a 1-week preliminary stability test (severe test), and has no problem in its storage stability, 2) a method of selectively producing two kinds of crystal forms of benzenesulfonate of compound A, and that 3) no mineral deposition in the stomach is observed even after a 4-week repeated oral administration.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is a divisional of U.S. patent application Ser.No. 13/384,590, filed on Jul. 16, 2010, the entire disclosure of whichis incorporated by reference herein.

TECHNICAL FIELD

The present invention relates to benzenesulfonate of2-[[[2-[(hydroxyacetyl)amino]-4-pyridinyl]methyl]thio]-N-[4-(trifluoromethoxy)phenyl]-3-pyridinecarboxamidethat is highly safe, excellent in storage stability, and useful as apharmaceutical, a crystal of the same, a crystal polymorph thereof, andproduction methods thereof. The present invention also relates to apharmaceutical containing at least one selected from the groupconsisting of benzenesulfonate of 2-[[[2-[(hydroxyacetyl)amino]-4-pyridinyl]methyl]thio]-N-[4-(trifluoromethoxy)phenyl]-3-pyridinecarboxamide,a crystal of the same, and a crystal polymorph thereof

BACKGROUND ART

Usually, for pharmaceutical products, safety, quality, and stable supplyare required, as well as a therapeutic efficacy on diseases. Therefore,for a compound serving as an active ingredient of a pharmaceuticalproduct, little side effect, excellent storage stability of the compoundin various conditions (light, temperature, humidity and so on), and easeof process control in a production stage of the pharmaceutical product(ease of handling) and the like are requested, and the compound will bea pharmaceutical product only when all of these requirements aresatisfied.

On the other hand, U.S. Patent Publication No. 2007/0149574 (PTL 1)describes that2-[[[2-[(hydroxyacetyl)amino]-4-pyridinyl]methyl]thio]-N-[4-(trifluoromethoxy)phenyl]-3-pyridinecarboxamideexhibits a cell proliferation inhibiting effect in a test system using aVEGF-induced HUVEC proliferation reaction evaluation system, exhibits atumor proliferation suppressing effect in a test system using atumor-bearing mouse model, exhibits a paw edema suppressing effect in atest system using a rat adjuvant arthritis model, and exhibits achoroidal neovascularization inhibiting effect in a test system using arat choroidal neovascularization model, and that, owing to thesepharmacologic effects,2-[[[2-[(hydroxyacetyl)amino]-4-pyridinyl]methyl]thio]-N-[4-(trifluoromethoxy)phenyl]-3-pyridinecarboxamideis useful as a pharmaceutical, and is especially expected as aprophylactic or therapeutic agent for diseases such as cancer,rheumatoid arthritis, age-related macular degeneration, diabeticretinopathy, diabetic macular edema and the like. PTL 1 also describesthat2-[[[2-[(hydroxyacetyl)amino]-4-pyridinyl]methyl]thio]-N-[4-(trifluoromethoxy)phenyl]-3-pyridinecarboxamidehas a property of a light yellow solid.

However, PTL 1 lacks concrete description of benzenesulfonate of2-[[[2-[(hydroxyacetyl)amino]-4-pyridinyl]methyl]thio]-N-[4-(trifluoromethoxy)phenyl]-3-pyridinecarboxamide,a crystal of the same, a crystal polymorph thereof and productionmethods thereof, and lacks description and suggestion of a problem that2-[[[2-[(hydroxyacetyl)amino]-4-pyridinyl]methyl]thio]-N-[4-(trifluoromethoxy)phenyl]-3-pyridinecarboxamidewill cause mineral deposition in the stomach when it is orallyadministered repeatedly.

CITATION LIST Patent Literature

-   PTL 1: U.S. Patent Publication No. 2007/0149574

SUMMARY OF INVENTION Technical Problem

In the course of developing2-[[[2-[(hydroxyacetyl)amino]-4-pyridinyl]methyl]thio]-N-[4-(trifluoromethoxy)phenyl]-3-pyridinecarboxamide(hereinafter, also referred to as “compound A”) that is useful as apharmaceutical, the present inventors found that there were thefollowing multiple problems: 1) compound A or its salt is difficult tobe recrystallized, the storage stability largely differs depending onthe kind of the salt, and it is very difficult to obtain a salt ofcompound A having excellent storage stability; 2) in a crystallizationprocess of compound A or its salt, it is very difficult to control acrystal polymorph, and 3) compound A (free body) causes mineraldeposition in the stomach when it is orally administered repeatedly.

Solution to Problem

In light of the above, the present inventors made diligent effortfocusing on the kind of the salt in compound A for solving all of theaforementioned problems 1) to 3).

As a result, the present inventors found that compound A formed a saltwith methanesulfonic acid, benzenesulfonic acid or p-toluenesulfonicacid. For examining the storage stability for these salts with compoundA, a 1-week preliminary stability test (severe test) was executed. As aresult, methanesulfonate of compound A decomposed by light, andp-toluenesulfonate decomposed by humidity, to cause a decrease in purity(decomposition) of about 1% to about 8%, demonstrating that these saltshave great problems in storage stability. On the other hand,benzenesulfonate of compound A did not show a decrease in purity(decomposition) by light, humidity and other factors in a similar test,demonstrating that it has very high storage stability.

Focusing on the existence of a crystal polymorph of benzenesulfonate ofcompound A, the present inventors also found that benzenesulfonate ofcompound A has at least two crystal forms and found a method ofproducing the two crystal forms selectively.

Further, the present inventors found that mineral deposition in thestomach was observed in a rat 1-week repeated oral administrationtoxicity test (30 mg/kg) of compound A, whereas mineral deposition inthe stomach was not observed in a rat 4-week repeated oraladministration toxicity test (30 mg/kg) of benzenesulfonate of compoundA, and accomplished the present invention. That is, the presentinvention is as follows.

The present invention is benzenesulfonate of2-[[[2-[(hydroxyacetyl)amino]-4-pyridinyl]methyl]thio]-N-[4-(trifluoromethoxy)phenyl]-3-pyridinecarboxamide.

The present invention also provides a method of producingbenzenesulfonate of2-[[[2-[(hydroxyacetyl)amino]-4-pyridinyl]methyl]thio]-N-[4-(trifluoromethoxy)phenyl]-3-pyridinecarboxamide,including the step of adding2-[[[2-[(hydroxyacetyl)amino]-4-pyridinyl]methyl]thio]-N-[4-(trifluoromethoxy)phenyl]-3-pyridinecarboxamideto an organic solvent solution containing benzenesulfonic acid.

The present invention also provides a method of producingbenzenesulfonate of2-[[[2-[(hydroxyacetyl)amino]-4-pyridinyl]methyl]thio]-N-[4-(trifluoromethoxy)phenyl]-3-pyridinecarboxamide,including the step of adding at least either of benzenesulfonic acid andits hydrate to an organic solvent solution containing2-[[[2-[(hydroxyacetyl)amino]-4-pyridinyl]methyl]thio]-N-[4-(trifluoromethoxy)phenyl]-3-pyridinecarboxamide.

Here, the organic solvent is preferably a non-protonic polar solvent orcyclic ether. Further, as the non-protonic polar solvent,dimethylsulfoxide or N,N-dimethylformamide is more preferred, and as thecyclic ether, tetrahydrofuran is more preferred.

The present invention is a crystal of benzenesulfonate of2-[[[2-[(hydroxyacetyl)amino]-4-pyridinyl]methyl]thio]-N-[4-(trifluoromethoxy)phenyl]-3-pyridinecarboxamide.

The present invention also provides a so-called α-form crystal ofbenzenesulfonate of2-[[[2-[(hydroxyacetyl)amino]-4-pyridinyl]methyl]thio]-N-[4-(trifluoromethoxy)phenyl]-3-pyridinecarboxamidehaving characteristic peaks at 4.4 angstroms, 3.8 angstroms and 2.3angstroms as a d value of powder X-ray diffraction pattern.

The present invention also provides a method of producing a so-calledα-form crystal of benzenesulfonate of2-[[[2-[(hydroxyacetyl)amino]-4-pyridinyl]methyl]thio]-N-[4-(trifluoromethoxy)phenyl]-3-pyridinecarboxamide,including the steps of: adding2-[[[2-[(hydroxyacetyl)amino]-4-pyridinyl]methyl]thio]-N-[4-(trifluoromethoxy)phenyl]-3-pyridinecarboxamideto a good solvent solution containing benzenesulfonic acid; andsequentially adding a poor solvent to the reaction solution.

The present invention also provides a method of producing a so-calledα-form crystal of benzenesulfonate of2-[[[2-[(hydroxyacetyl)amino]-4-pyridinyl]methyl]thio]-N-[4-(trifluoromethoxy)phenyl]-3-pyridinecarboxamide,including the steps of: adding at least either of benzenesulfonic acidand its hydrate to a good solvent solution containing2-[[[2-[(hydroxyacetyl)amino]-4-pyridinyl]methyl]thio]-N-[4-(trifluoromethoxy)phenyl]-3-pyridinecarboxamide;and sequentially adding a poor solvent to the reaction solution.

Here, the good solvent is preferably a non-protonic polar solvent, andmore preferably dimethylsulfoxide or N,N-dimethylformamide.

Here, the poor solvent is preferably a solvent that substantially failsto dissolve benzenesulfonate of2-[[[2-[(hydroxyacetyl)amino]-4-pyridinyl]methyl]thio]-N-[4-(trifluoromethoxy)phenyl]-3-pyridinecarboxamideat room temperature, and is more preferably water, a lower alkylalcohol, a lower alkyl ketone or a lower alkyl carboxylic acid ester,and the solvent is further preferably water, ethanol, acetone or ethylacetate, and particularly preferably ethanol.

The present invention also provides a method of producing a so-calledα-form crystal of benzenesulfonate of2-[[[2-[(hydroxyacetyl)amino]-4-pyridinyl]methyl]thio]-N-[4-(trifluoromethoxy)phenyl]-3-pyridinecarboxamide,including the step of adding a poor solvent to a good solvent solutioncontaining benzenesulfonate of2-[[[2-[(hydroxyacetyl)amino]-4-pyridinyl]methyl]thio]-N-[4-(trifluoromethoxy)phenyl]-3-pyridinecarboxamide.

Here, the good solvent is preferably a non-protonic polar solvent, andmore preferably dimethylsulfoxide or N,N-dimethylformamide.

Here, the poor solvent is preferably a solvent that substantially failsto dissolve benzenesulfonate of2-[[[2-[(hydroxyacetyl)amino]-4-pyridinyl]methyl]thio]-N-[4-(trifluoromethoxy)phenyl]-3-pyridinecarboxamideat room temperature, and is more preferably water, a lower alkylalcohol, a lower alkyl ketone or a lower alkyl carboxylic acid ester,and the solvent is particularly preferably water, ethanol, acetone orethyl acetate.

The present invention also provides a method of producing a so-calledα-form crystal of benzenesulfonate of2-[[[2-[(hydroxyacetyl)amino]-4-pyridinyl]methyl]thio]-N-[4-(trifluoromethoxy)phenyl]-3-pyridinecarboxamide,including the steps of: adding and dissolving benzenesulfonate of2-[[[2-[(hydroxyacetyl)amino]-4-pyridinyl]methyl]thio]-N-[4-(trifluoromethoxy)phenyl]-3-pyridinecarboxamidein a warmed lower alcohol; and sequentially cooling the lower alcoholsolution.

Here, the lower alcohol is preferably methanol or ethanol.

The present invention also provides a so-called β-form crystal ofbenzenesulfonate of2-[[[2-[(hydroxyacetyl)amino]-4-pyridinyl]methyl]thio]-N-[4-(trifluoromethoxy)phenyl]-3-pyridinecarboxamidehaving characteristic peaks at 8.1 angstroms, 6.8 angstroms, 4.1angstroms and 4.0 angstroms as a d value of powder X-ray diffractionpattern.

The present invention also provides a method of producing a so-calledβ-form crystal of benzenesulfonate of2-[[[2-[(hydroxyacetyl)amino]-4-pyridinyl]methyl]thio]-N-[4-(trifluoromethoxy)phenyl]-3-pyridinecarboxamide,including the step of adding2-[[[2-[(hydroxyacetyl)amino]-4-pyridinyl]methyl]thio]-N-[4-(trifluoromethoxy)phenyl]-3-pyridinecarboxamideto a cyclic ether solution containing benzenesulfonic acid.

The present invention also provides a method of producing a so-calledβ-form crystal of benzenesulfonate of2-[[[2-[(hydroxyacetyl)amino]-4-pyridinyl]methyl]thio]-N-[4-(trifluoromethoxy)phenyl]-3-pyridinecarboxamide,including the step of adding at least either of benzenesulfonic acid andits hydrate to a cyclic ether solution containing2-[[[2-[(hydroxyacetyl)amino]-4-pyridinyl]methyl]thio]-N-[4-(trifluoromethoxy)phenyl]-3-pyridinecarboxamide.

Here, the cyclic ether is preferably tetrahydrofuran.

The present invention also provides a pharmaceutical containing as anactive ingredient, at least one selected from the group consisting ofany of the aforementioned benzenesulfonates, a crystal of the same, anda so-called α-form crystal and a so-called β-form crystal thereof

The present invention also provides an oral or parenteral agentcontaining as an active ingredient, at least one selected from the groupconsisting of any of the aforementioned benzenesulfonates, a crystal ofthe same, and a so-called α-form crystal and a so-called β-form crystalthereof.

Advantageous Effects of Invention

The present invention provides benzenesulfonate of compound A that ishighly safe, excellent in storage stability, and useful as apharmaceutical, a crystal of the same, a crystal polymorph thereof, andproduction methods thereof The present invention also provides apharmaceutical containing at least one selected from the groupconsisting of benzenesulfonate of compound A, a crystal of the same, anda crystal polymorph thereof

DESCRIPTION OF EMBODIMENTS

In the present invention,“2-[[[2-[(hydroxyacetyl)amino]-4-pyridinyl]methyl]thio]-N-[4-(trifluoromethoxy)phenyl]-3-pyridinecarboxamide”(compound A) means a compound represented by the following chemicalstructure formula (1).

Compound A can be produced according to, but not limited to, theproduction method described in U.S. Patent Application Publication No.2007/0149574 specification.

In the present invention, “benzenesulfonate of compound A” means acompound formed by the above chemical structure formula (1) andbenzenesulfonic acid. A constituting ratio between compound A andbenzenesulfonic acid is preferably 1:1 or 1:2, and is particularlypreferably 1:1. Further, when the constituting ratio between compound Aand benzenesulfonic acid is 1:1, “benzenesulfonate of compound A” isdesirably a compound represented by the following chemical structuralformula (2).

(1) Production Method of Benzenesulfonate of Compound A

Benzenesulfonate of compound A can be produced by:

(1a) adding compound A to an organic solvent solution containingbenzenesulfonic acid, or

(1b) adding at least either of benzenesulfonic acid and its hydrate toan organic solvent solution containing compound A.

While the temperature at the time of executing (1a) or (1b) is notparticularly limited insofar as salt formation progresses, it isexecuted preferably under ice cooling or at room temperature, and morepreferably at 15 to 30° C.

The time of executing (1a) or (1b) is not particularly limited insofaras it is enough to allow progression of salt formation.

Further, benzenesulfonate of compound A generated in this operation canbe isolated and/or purified by a widely used treatment method and/orpurification method, for example, by using techniques such asconcentration under reduced pressure, crystallization in water, anorganic solvent and the like, filtration, washing, drying under reducedpressure and so on.

As the “organic solvent” in (1a) or (1b), any organic solvent capable ofdissolving compound A may be used without any limitation, however, anon-protonic polar solvent or cycle ether is preferred.

As the “non-protonic polar solvent”, any polar solvent not having aproton-donating ability may be used without any limitation, and forexample, dimethylsulfoxide, N,N-dimethylformamide,N,N-dimethylacetamide, N-methylpyrrolidone, hexamethylphosphoramide andthe like can be recited. Among these, dimethylsulfoxide orN,N-dimethylformamide is particularly preferred.

As the “cyclic ether”, any cyclic ether containing 1 to 6 carbon atom(s)and one or two oxygen atom(s) may be used without any limitation, andfor example, oxirane, oxetane, tetrahydrofuran, tetrahydropyran,[1,4]dioxane, oxepane, oxocane and the like are recited. Among these,tetrahydrofuran is particularly preferred.

(2) Production Method of So-Called α-Form Crystal of Benzenesulfonate ofCompound A

A so-called α-form crystal of benzenesulfonate of compound A can beproduced by:

(2a) adding compound A to a good solvent solution containingbenzenesulfonic acid, followed by adding a poor solvent to the reactionsolution, or

(2b) adding at least either of benzenesulfonic acid and its hydrate to agood solvent solution containing compound A, followed by adding a poorsolvent to the reaction solution, or

(2c) adding a poor solvent to a good solvent solution containingbenzenesulfonate of compound A, or

(2d) adding and dissolving benzenesulfonate of compound A in a warmedlower alcohol, followed by cooling the lower alcohol solution.

While the temperature at the time of executing (2a) or (2b) is notparticularly limited insofar as salt formation progresses, it isexecuted preferably under ice cooling or at room temperature, and morepreferably at 15 to 30° C.

While the temperature during and after the addition of the poor solventin executing (2a), (2b) or (2c) is not particularly limited insofar ascrystallization progresses, it is executed preferably at roomtemperature, and more preferably at 15 to 30° C.

While the warming in executing (2d) is not particularly limited insofaras it is such a degree of warming that allows (complete) dissolution ofbenzenesulfonate of compound A in a lower alcohol, the warmingtemperature is preferably 40 to 70° C., and more preferably 45 to 65° C.

While the cooling after the warming may be conducted at any temperaturewithout any limitation insofar as crystallization progresses, it ispreferably executed under ice cooling or at room temperature (allowingto cool), and more preferably at 15 to 30° C.

The reaction time in executing (2a) or (2b) is not particularly limitedinsofar as it is enough for the reaction to progress.

While the crystallization time after the addition of the poor solvent inexecuting (2a), (2b), (2c) or (2d) is not particularly limited insofaras crystallization progresses, it is executed preferably for 0.25 hoursto 48 hours, and more preferably 3 hours to 24 hours.

Further, a so-called α-form crystal of benzenesulfonate of compound Agenerated in the reaction or the like can be isolated and/or purified bya widely used treatment method and/or purification method, for example,by using techniques such as concentration under reduced pressure,crystallization in water, an organic solvent and the like, filtration,washing, drying under reduced pressure and so on.

The “good solvent” in (2a), (2b) or (2c) means “an organic solventcapable of dissolving benzenesulfonate of compound A”, and preferably, anon-protonic polar solvent is recited, and particularly preferably,dimethylsulfoxide or N,N-dimethylformamide is recited.

Here, the “non-protonic polar solvent” is not particularly limitedinsofar as it is a polar solvent not having a proton donating ability,and for example, dimethylsulfoxide, N,N-dimethylformamide,N,N-dimethylacetamide, N-methylpyrrolidone or hexamethylphosphoramide isrecited, and among these, dimethylsulfoxide or N,N-dimethylformamide ispreferred.

The “poor solvent” means a “solvent substantially not dissolvingbenzenesulfonate of compound A at room temperature”, and for example,water, a lower alcohol, a lower alkyl ketone or a lower alkyl carboxylicacid ester is recited, and among these, a lower alcohol is preferred.

Here, the “lower alcohol” means an alcohol having 1 to 6 carbon atom(s),and for example, methanol, ethanol, propanol, isopropanol, butanol,isobutanol or tert-butanol is recited, and among these methanol orethanol is preferred.

The “lower alkyl ketone” means an alkyl ketone having 1 to 13,preferably 1 to 7 carbon atom(s), and for example, acetone,methylethylketone or diethylketone is recited, and among these acetoneis preferred. The “lower alkyl carboxylic acid ester” means an alkylcarboxylic acid ester having 1 to 13, preferably 1 to 7 carbon atom(s),and for example, ethyl acetate, methyl acetate or isopropyl acetate isrecited, and among these ethyl acetate is preferred.

As to the ratio between the “good solvent” and the “poor solvent”, theratio of the good solvent and the poor solvent may be appropriatelyselected within the range of 10:1 to 1:10 depending on the kinds of thegood solvent and the poor solvent. For example, when the good solvent isdimethylsulfoxide and the poor solvent is water, the ratio of these ispreferably in the range of 3:1 to 1:1, and more preferably in the rangeof 2:1. When the good solvent is dimethylsulfoxide and the poor solventis ethanol, the ratio of these is preferably in the range of 1:3 to 1:7,more preferably in the range of 1:4 to 1:6, and particularly preferably1:5. When the good solvent is dimethylsulfoxide and the poor solvent isacetone, the ratio of these is preferably in the range of 1:3 to 1:7,more preferably in the range of 1:4 to 1:6, and particularly preferably1:5. When the good solvent is dimethylsulfoxide and the poor solvent isethyl acetate, the ratio of these is preferably in the range of 1:2 to1:6, more preferably in the range of 1:3 to 1:5, and particularlypreferably 1:4.

In (2d), the “lower alcohol” means an alcohol having 1 to 6 carbonatom(s), and for example, methanol, ethanol, propanol, isopropanol,butanol, isobutanol or tert-butanol is recited, and among these methanolor ethanol is preferred. (3) Production method of a so-called β-formcrystal of benzenesulfonate of compound A

A so-called β-form crystal of benzenesulfonate of compound A can beproduced by:

(3a) adding compound A to a cyclic ether solution containingbenzenesulfonic acid, or

(3b) adding at least either of benzenesulfonic acid and its hydrate to acyclic ether solution containing compound A.

While the temperature at the time of executing (3a) or (3b) is notparticularly limited insofar as salt formation progresses, it isexecuted preferably under ice cooling or at room temperature, and morepreferably at 15 to 30° C.

The reaction time in executing (3a) or (3b) is not particularly limitedinsofar as it is enough for the reaction to progress.

Further, a so-called β-form crystal of benzenesulfonate of compound Agenerated in the reaction or the like can be isolated and/or purified bya widely used treatment method and/or purification method, for example,by using techniques such as concentration under reduced pressure,crystallization in water, an organic solvent and the like, filtration,washing, drying under reduced pressure and so on.

The “cyclic ether” in (3a) or (3b) is not particularly limited insofaras it is a cyclic ether capable of dissolving compound A and being apoor solvent with respect to benzenesulfonate of compound A, and cyclicethers containing 2 to 6 carbon atom(s) and one or two oxygen atom(s)are recited. Preferably, oxirane, oxetane, tetrahydrofuran,tetrahydropyran, [1,4]dioxane, oxepane, oxocane or the like are recited,and particularly preferably, tetrahydrofuran is recited.

While two forms of crystals called an α-form and a β-form exist ascrystals of benzenesulfonate of compound A, crystal polymorphs otherthan these, if exist, are also involved in crystals of benzenesulfonateof compound A of the present invention.

In the following, benzenesulfonate of compound A, a crystal of the sameand a crystal polymorph thereof (including a so-called α-form crystaland a so-called β-form crystal) are also referred to as a “presentcompound”.

While the present compound can absorb water and have adsorbed water, orbecome a hydrate when it is left still in atmospheric air orrecrystallized, such a hydrate is also involved in the presentinvention.

Since the present compound exhibits a cell proliferation inhibitingeffect in a test system using a VEGF-induced HUVEC proliferationreaction evaluation system, exhibits a tumor proliferation suppressingeffect in a test system using a tumor-bearing mouse model, exhibits apaw edema suppressing effect in a test system using a rat adjuvantarthritis model, and exhibits a choroidal neovascularization inhibitingeffect in a test system using a rat choroidal neovascularization model,it is useful as a pharmaceutical, and is especially useful as aprophylactic or therapeutic agent for diseases such as cancer,rheumatoid arthritis, age-related macular degeneration, diabeticretinopathy, diabetic macular edema and the like. The pharmaceutical isfor use in a warm-blooded animal, and preferably for a human being.

When the present compound is used as a prophylactic or therapeutic drugfor the aforementioned diseases, the present compound can beadministered either orally or parenterally. As a dosage form, tablet,capsule, granule and powder are recited as oral agents, and injection,eye drop, nasal drop, transdermally absorbable agent, aerosol (including“inhalant”) and the like are recited as parenteral agents, and they maybe formulated using widely used techniques.

For example, oral agents such as tablet, capsule, granule and powder canbe prepared while using excipients such as lactose, mannitol, starch,crystalline cellulose, light anhydrous silicic acid, calcium carbonateand calcium hydrogen phosphate, lubricants such as stearic acid,magnesium stearate and talc, binders such as starch, hydroxypropylcellulose, hypromellose and polyvinyl pyrrolidone, disintegrants such ascarboxymethyl cellulose, low substitution degree hydroxypropyl celluloseand calcium citrate, coating agents such as hypromellose, hydroxymethylcellulose, macrogol and silicone resin, stabilizers such as ethylparaoxybenzoate and benzyl alcohol, flavoring agents such as sweetener,acidulant and flavor, and the like as necessary.

Further, parenteral agents such as injection and eye drop can beprepared while using isotonizing agents such as sodium chloride,concentrated glycerin, propylene glycol, polyethylene glycol, potassiumchloride, sorbitol and mannitol, buffering agents such as sodiumphosphate, sodium hydrogen phosphate, sodium acetate, citric acid,glacial acetic acid and trometamol, surfactants such as polyoxyethylenesorbitan monooleate, polyoxyl 40 stearate and polyoxyethylenehydrogenated castor oil, stabilizing agents such as sodium citrate andsodium edetate, preservatives such as benzalkonium chloride, paraben,benzethonium chloride, paraoxybenzoic acid ester, sodium benzoate andchlorobutanol, pH modifiers such as hydrochloric acid, citric acid,phosphoric acid, glacial acetic acid, sodium hydroxide, sodium carbonateand sodium hydrogen carbonate, soothing agents such as benzyl alcohol,thickening agents such as hypromellose, and the like as necessary.

A dosage of the present compound can be appropriately selected and usedaccording to the symptom, age, dosage form and the like. For example, anoral agent may be typically administered in a dosage of 0.01 to 1000 mg,preferably 1 to 100 mg per day by a single dose or in several doses. Aneye drop can be typically administered in a concentration of 0.0001 to10% (w/v), preferably 0.01 to 5% (w/v) by a single dose or in severaldoses.

Hereinafter, production examples of the present compound, a storagestability test and a result of the same, a side effect verification testand a result of the same, and formulation examples will be described,however, it is to be noted that these examples are given for betterunderstanding of the present invention and not for limiting the scope ofthe present invention. Hereinafter, “¹H-NMR” means “proton nuclearmagnetic resonance”, “PXRD” means “powder X-ray diffraction”, “DSC”means “differential scanning calorimeter measurement”, “TGA” means“thermogravimetric apparatus”, and “RH” means “relative humidity”.

PRODUCTION EXAMPLES Example 1 Production Method of Benzenesulfonate ofCompound A

To compound A (200 mg) was added tetrahydrofuran (2 mL) and stirred atroom temperature. After confirming dissolution, benzenesulfonic acidmonohydrate (85 mg) was added at the same temperature. After end of saltformation, the solvent was distilled off under reduced pressure. To theconcentrated residue was added ethyl acetate, and the precipitated solidwas collected by filtration, and dried under reduced pressure to obtainbenzenesulfonate of compound A in white (171 mg).

¹H-NMR (500 MHz,DMSO-d₆)

δ 4.02 (s,2H), 4.44 (s,2H), 7.17 (dd,J=4.9,1.5 Hz,1H), 7.28-7.38 (m,5H),7.58-7.60 (m,2H), 7.71 (d,J=1.2 Hz,1H), 7.80-7.82 (m,2H), 7.99(dd,J=7.6,1.8 Hz,1H), 8.20 (d,J=5.2 Hz,2H), 8.60 (dd,J=4.9,1.8 Hz,1H),10.66 (s,1H)

Example 2 Production Method 1 of Benzenesulfonate of Compound A (αCrystal) (Ethyl Acetate/DMSO)

To compound A (503 mg) was added dimethylsulfoxide (2.0 mL) and stirredat room temperature. After confirming dissolution, benzenesulfonic acidmonohydrate (207 mg) was added at the same temperature, and stirred foranother 1.25 hours. Sequentially, ethyl acetate (15 mL) was added, andstirred for another 3.5 hours. The precipitated solid was collected byfiltration, and dried under reduced pressure, to obtain benzenesulfonateof compound A in white (510 mg).

¹H-NMR (500 MHz,DMSO-d₆):

δ 4.05 (s,2H), 4.47 (s,2H), 7.28-7.38 (m,7H), 7.58-7.60 (m,2H), 7.81(d,J=9.2 Hz,2H), 8.01 (dd,J=7.6,1.8 Hz,1H), 8.16 (s,1H), 8.24 (d,J=5.5Hz,1H), 8.59 (dd,J=4.9,1.5 Hz,1H), 10.08 (bs,1H), 10.66 (s,1H)

PXRD:

TABLE 1 Peak Angle Angstrom 2θ° d = 4.4627 19.878 d = 4.3709 20.300 d =3.8408 23.139 d = 2.3377 38.477

TGA:

Endothermic peak: 206.2° C.

Example 3 Production Method 2 of Benzenesulfonate of Compound A (αCrystal) (Ethanol/DMSO)

To compound A (505 mg) was added dimethylsulfoxide (2.0 mL) and stirredat room temperature. After confirming dissolution, benzenesulfonic acidmonohydrate (200 mg) was added at the same temperature, and stirred foranother 1.25 hours. Sequentially, ethanol (10 mL) was added, and stirredfor another 2.5 hours. The precipitated solid was collected byfiltration, and dried under reduced pressure, to obtain benzenesulfonateof compound A in white (482 mg).

¹H-NMR (500 MHz,DMSO-d₆):

δ 4.07 (s,2H), 4.49 (s,2H), 7.29-7.39 (m,7H), 7.58-7.60 (m,2H), 7.81(d,J=9.2 Hz,2H), 8.03 (dd,J=7.6,1.8 Hz,1H), 8.15 (s,1H), 8.27 (d,J=5.5Hz,1H), 8.59 (dd,J=4.9,1.8 Hz,1H), 10.32 (bs,1H), 10.67 (s,1H)

PXRD:

TABLE 2 Peak Angle Angstrom 2θ° d = 4.4670 19.859 d = 4.3711 20.300 d =3.8438 23.120 d = 2.3377 38.478

TGA:

Endothermic peak: 207.7° C.

Example 4 Production Method 3 of Benzenesulfonate of Compound A (αCrystal) (Ethanol/DMSO)

To benzenesulfonic acid monohydrate (388 g) was added dimethylsulfoxide(1650 g) at room temperature (internal temperature 28° C.).Sequentially, compound A (750 g) was added at the same temperature.After stirring for 2.0 hours at room temperature, the solution wasfiltered. Sequentially, to the filtrate was added ethanol (5938 g) andstirred for 2.0 hours at room temperature. The precipitated solid wascollected by filtration, and dried under reduced pressure, to obtainbenzenesulfonate of compound A in white (820 g).

¹H-NMR (500 MHz,DMSO-d₆):

δ 4.08 (s,2H), 4.49 (s,2H), 7.29-7.39 (m,7H), 7.58-7.61 (m,2H), 7.81(d,J=9.2 Hz,2H), 8.03 (dd,J=7.8,1.8 Hz,1H), 8.14 (s,1H), 8.27 (d,J=5.5Hz,1H), 8.59 (dd,J=5.0,1.8 Hz,1H), 10.40 (bs,1H), 10.66 (s,1H)

PXRD:

TABLE 3 Peak Angle Angstrom 2θ° d = 4.4579 19.900 d = 4.3624 20.340 d =3.8405 23.141 d = 2.3364 38.500

Example 5 Production Method 4 of Benzenesulfonate of Compound A (αCrystal) (Methanol, Leaving Still at Room Temperature)

To benzenesulfonate of compound A (99 mg) was added methanol (3 mL), andthen stirred at an external temperature of 65° C. for 4 minutes. Afterconfirming dissolution, the reaction was left still overnight at roomtemperature. The precipitated solid was collected by filtration, anddried under reduced pressure, to obtain benzenesulfonate of compound Ain white (50 mg).

¹H-NMR (500 MHz,DMSO-d₆)

δ 4.12 (s,2H), 4.52 (s,2H), 7.30 (dd,J=4.6,1.5 Hz,1H), 7.31-7.34 (m,4H),7.38 (d,J=8.6 Hz,2H), 7.47 (d,J=5.8 Hz,1H), 7.60-7.62 (m,2H), 7.81-7.83(m,2H), 8.05 (dd,J=7.6,1.5 Hz,1H), 8.12 (s,1H), 10.68 (s,1H), 10.83(s,1H)

Example 6 Production Method 5 of Benzenesulfonate of Compound A (αCrystal) (Ethanol, Leaving Still at Room Temperature)

To benzenesulfonate of compound A (99 mg) was added ethanol (5 mL), andthen stirred at an external temperature of 85° C. for 3 minutes. Afterconfirming dissolution, the reaction was left still overnight at roomtemperature. The precipitated solid was collected by filtration, anddried under reduced pressure, to obtain benzenesulfonate of compound Ain white (66 mg).

¹H-NMR (500 MHz,DMSO-d₆)

δ 4.11 (s,2H), 4.52 (s,2H), 7.30 (dd,J=4.6,2.4 Hz,1H), 7.31-7.34 (m,4H),7.38 (d,J=8.6 Hz,2H), 7.44 (s,1H), 7.60-7.61 (m,2H), 7.81-7.83 (m,2H),8.05 (d,J=7.6 Hz,1H), 8.12 (s,1H), 10.67 (s,1H), 10.83 (bs,1H)

Example 7 Production Method 6 of Benzenesulfonate of Compound A (αCrystal) (Ethyl Acetate/DMSO, Leaving Still at Room Temperature)

To benzenesulfonate of compound A (1.0 g) was added dimethylsulfoxide(1.5 mL), and then stirred at an internal temperature of 50° C. for 11minutes. After confirming dissolution, ethyl acetate (6.0 mL) was added.After leaving still overnight at room temperature, the precipitatedsolid was collected by filtration, and dried under reduced pressure, toobtain benzenesulfonate of compound A in white (619 mg).

¹H-NMR (500 MHz,DMSO-d₆):

δ 4.07 (s,2H), 4.49 (s,2H), 7.29-7.39 (m,7H), 7.59-7.61 (m,2H), 7.81(d,J=9.2 Hz,2H), 8.03 (d,J=7.6 Hz,1H), 8.14 (s,1H), 8.26 (d,J=5.5Hz,1H), 8.58 (dd,J=4.9,1.8 Hz,1H), 10.35 (bs,1H), 10.66 (s,1H)

PXRD:

TABLE 4 Peak Angle Angstrom 2θ° d = 4.4665 19.861 d = 4.3670 20.319 d =3.8408 23.138 d = 2.3399 38.440

TGA:

Endothermic peak: 207.2° C.

Example 8 Production Method 7 of Benzenesulfonate of Compound A (αCrystal) (Ethyl Acetate/DMSO, Leaving Still at Room Temperature)

To benzenesulfonate of compound A (1.0 g) was added dimethylsulfoxide(1.5 mL), and then stirred at an internal temperature of 50° C. for 6minutes. After confirming dissolution, ethyl acetate (6.0 mL) was added.After stirring for 4.5 hours at room temperature, the precipitated solidwas collected by filtration, and dried under reduced pressure, to obtainbenzenesulfonate of compound A in white (701 mg).

¹H-NMR(500 MHz,DMSO-d₆):

δ 4.08 (s,2H), 4.49 (s,2H), 7.29-7.39 (m,7H), 7.59-7.61 (m,2H), 7.81(d,J=9.2 Hz,2H), 8.03 (d,J=7.6 Hz,1H), 8.14 (s,1H), 8.27 (d,J=5.8Hz,1H), 8.59 (dd,J=4.9,1.8 Hz,1H), 10.39 (bs,1H), 10.66 (s,1H)

PXRD:

TABLE 5 Peak Angle Angstrom 2θ° d = 4.4627 19.879 d = 4.3673 20.318 d =3.8437 23.121 d = 2.3366 38.495

TGA:

Endothermic peak: 209.2° C.

Example 9 Production Method 8 of Benzenesulfonate of Compound A (αCrystal) (Ethyl Acetate/DMSO, Leaving Still Under Ice Cooling)

To benzenesulfonate of compound A (1.0 g) was added dimethylsulfoxide(1.5 mL), and then stirred at an internal temperature of 50° C. for 6minutes. After confirming dissolution, ethyl acetate (6.0 mL) was added.After leaving still overnight under ice cooling (internal temperature 5°C.), the precipitated solid was collected by filtration, and dried underreduced pressure, to obtain benzenesulfonate of compound A in white (227mg).

¹H-NMR (500 MHz,DMSO-d₆):

δ 4.08 (s,2H), 4.49 (s,2H), 7.30-7.39 (m,7H), 7.59-7.61 (m,2H), 7.81(d,J=9.2 Hz,2H), 8.02 (d,J=6.4 Hz,1H), 8.14 (s,1H), 8.27 (d,J=5.5Hz,1H), 8.59 (m,1H), 10.36 (bs,1H), 10.66 (s,1H)

PXRD:

TABLE 6 Peak Angle Angstrom 2θ° d = 4.4670 19.859 d = 4.3664 20.321 d =3.8409 23.138 d = 2.3375 38.480

TGA:

Endothermic peak: 207.1° C.

Example 10 Production Method 9 of Benzenesulfonate of Compound A (αCrystal) (Acetone/DMSO, Stirring at Room Temperature)

To benzenesulfonate of compound A (1.0 g) was added dimethylsulfoxide(1.5 mL), and then stirred at an internal temperature of 50° C. for 5minutes. After confirming dissolution, acetone (7.0 mL) was added. Afterstirring for 5.0 hours at room temperature, the precipitated solid wascollected by filtration, and dried under reduced pressure, to obtainbenzenesulfonate of compound A in white (629 mg).

¹H-NMR (500 MHz,DMSO-d₆):

δ 4.08 (s,2H), 4.49 (s,2H), 7.29-7.39 (m,7H), 7.59-7.61 (m,2H), 7.81(d,J=9.2 Hz,2H), 8.03 (dd,J=7.6,1.8 Hz,1H), 8.14 (s,1H), 8.27 (d,J=5.8Hz,1H), 8.59 (dd,J=4.9,1.8 Hz,1H), 10.39 (bs,1H), 10.66 (s,1H)

PXRD:

TABLE 7 Peak Angle Angstrom 2θ° d = 4.4628 19.878 d = 4.3746 20.283 d =3.8378 23.157 d = 2.3376 38.480

Example 11 Production Method 10 of Benzenesulfonate of Compound A (αCrystal) (Acetone/DMSO, Leaving Still under Ice Cooling)

To benzenesulfonate of compound A (1.0 g) was added dimethylsulfoxide(1.5 mL), and then stirred at an internal temperature of 50° C. for 5minutes. After confirming dissolution, acetone (7.0 mL) was added. Afterleaving still overnight under ice cooling (internal temperature 5° C.),the precipitated solid was collected by filtration, and dried underreduced pressure, to obtain benzenesulfonate of compound A in white (224mg).

¹H-NMR (500 MHz,DMSO-d₆):

δ 4.08 (s,2H), 4.49 (s,2H), 7.29-7.39 (m,7H), 7.59-7.61 (m,2H), 7.81(d,J=8.9 Hz,2H), 8.03 (dd,J=7.6,1.5 Hz,1H), 8.14 (s,1H), 8.27 (d,J=5.8Hz,1H), 8.59 (dd,J=4.9,1.5 Hz,1H), 10.37 (bs,1H), 10.66 (s,1H)

PXRD:

TABLE 8 Peak Angle Angstrom 2θ° d = 4.4712 19.840 d = 4.3709 20.300 d =3.8472 23.100 d = 2.3399 38.440

Example 12 Production Method 11 of Benzenesulfonate of Compound A (αCrystal) (Water/DMSO, Leaving Still at Room Temperature)

To benzenesulfonate of compound A (1.0 g) was added dimethylsulfoxide(1.5 mL), and then stirred at an internal temperature of 50° C. for 6minutes. After confirming dissolution, water (0.8 mL) was added. Afterleaving still for 1 hour at room temperature, the precipitated solid wascollected by filtration, and dried under reduced pressure, to obtainbenzenesulfonate of compound A in white (928 mg).

¹H-NMR (500 MHz,DMSO-d₆):

δ 4.08 (s,2H), 4.49 (s,2H), 7.29-7.39 (m,7H), 7.59-7.61 (m,2H), 7.81(d,J=9.2 Hz,2H), 8.03 (dd,J=7.6,1.5 Hz,1H), 8.14 (s,1H), 8.27 (d,J=5.8Hz,1H), 8.59 (dd,J=4.9,1.8 Hz,1H), 10.36 (bs,1H), 10.66 (s,1H)

PXRD:

TABLE 9 Peak Angle Angstrom 2θ° d = 4.4673 19.858 d = 4.3710 20.300 d =3.8469 23.101 d = 2.3376 38.479

TGA:

Endothermic peak: 205.5° C.

Example 13 Production Method 12 of Benzenesulfonate of Compound A (αCrystal) (Water/DMSO, Stirring at Room Temperature)

To benzenesulfonate of compound A (1.0 g) was added dimethylsulfoxide(1.5 mL), and then stirred at an internal temperature of 50° C. for 5minutes. After confirming dissolution, water (0.8 mL) was added. Afterstirring for 0.5 hours at room temperature, the precipitated solid wascollected by filtration, and dried under reduced pressure, to obtainbenzenesulfonate of compound A in white (910 mg).

¹H-NMR (500 MHz,DMSO-d₆):

δ 4.08 (s,2H), 4.49 (s,2H), 7.29-7.39 (m,7H), 7.59-7.61 (m,2H), 7.81(d,J=9.2 Hz,2H), 8.03 (dd,J=7.6,1.8 Hz,1H), 8.14 (s,1H), 8.27 (d,J=5.8Hz,1H), 8.59 (dd,J=4.9,1.5 Hz,1H), 10.40 (bs,1H), 10.66 (s,1H)

PXRD:

TABLE 10 Peak Angle Angstrom 2θ° d = 4.4662 19.863 d = 4.3672 20.318 d =3.8439 23.120 d = 2.3376 38.479

Example 14 Production Method 13 of Benzenesulfonate of Compound A (αCrystal) (Water/DMSO, Leaving Still Under Ice Cooling)

To benzenesulfonate of compound A (1.0 g) was added dimethylsulfoxide(1.5 mL), and then stirred at an internal temperature of 50° C. for 5minutes. After confirming dissolution, water (0.8 mL) was added. Afterleaving still overnight under ice cooling (internal temperature 7° C.),the precipitated solid was collected by filtration, and dried underreduced pressure, to obtain benzenesulfonate of compound A in white (927mg).

¹H-NMR (500 MHz,DMSO-d₆):

δ 4.08 (s,2H), 4.49 (s,2H), 7.29-7.39 (m,7H), 7.59-7.61 (m,2H), 7.81(d,J=8.9 Hz,2H), 8.03 (dd,J=7.6,1.5 Hz,1H), 8.14 (s,1H), 8.27 (d,J=5.5Hz,1H), 8.59 (dd,J=4.9,1.5 Hz,1H), 10.41 (bs,1H), 10.66 (s,1H)

PXRD:

TABLE 11 Peak Angle Angstrom 2θ° d = 4.4628 19.878 d = 4.3710 20.300 d =3.8407 23.139 d = 2.3366 38.496

Example 15 Production Method 14 of Benzenesulfonate of Compound A (αCrystal) (Ethanol/DMSO, Leaving Still at Room Temperature)

To benzenesulfonate of compound A (1.0 g) were added dimethylsulfoxide(2.7 mL) and ethanol (6.0 mL), and then stirred at an internaltemperature of 50° C. for 5 minutes. After leaving still overnight atroom temperature, the precipitated solid was collected by filtration,and dried under reduced pressure, to obtain benzenesulfonate of compoundA in white (104 mg).

¹H-NMR (500 MHz,DMSO-d₆):

δ 4.08 (s,2H), 4.49 (s,2H), 7.29-7.39 (m,7H), 7.59-7.61 (m,2H), 7.81(d,J=9.2 Hz,2H), 8.03 (dd,J=7.6,1.8 Hz,1H), 8.14 (s,1H), 8.27 (d,J=6.1Hz,1H), 8.59 (dd,J=4.9,1.8 Hz,1H), 10.39 (bs,1H), 10.66 (s,1H)

TGA:

Endothermic peak: 210.1° C.

Example 16 Production Method 15 of Benzenesulfonate of Compound A (αCrystal) (Ethanol/DMSO, Stirring at Room Temperature)

To benzenesulfonate of compound A (1.0 g) was added dimethylsulfoxide(2.5 mL), and then stirred at an internal temperature of 50° C. for 5minutes. After confirming dissolution, ethanol (3.0 mL) was added. Afterstirring at room temperature for 5.0 hours, the precipitated solid wascollected by filtration, and dried under reduced pressure, to obtainbenzenesulfonate of compound A in white (71 mg).

¹H-NMR (500 MHz,DMSO-d₆):

δ 4.08 (s,2H), 4.49 (s,2H), 7.29-7.39 (m,7H), 7.59-7.61 (m,2H), 7.81(d,J=9.2 Hz,2H), 8.03 (dd,J=7.6,1.5 Hz,1H), 8.14 (s,1H), 8.27 (d,J=5.8Hz,1H), 8.59 (dd,J=4.9,1.8 Hz,1H), 10.40 (bs,1H), 10.66 (s,1H)

TGA:

Endothermic peak: 210.7° C.

Example 17 Production Method 16 of Benzenesulfonate of Compound A (αcrystal) (Ethanol/DMSO, Leaving Still Under Ice Cooling)

To benzenesulfonate of compound A (1.0 g) were added dimethylsulfoxide(3.3 mL) and ethanol (6.0 mL), and then stirred at an internaltemperature of 50° C. for 15 minutes. After leaving still overnightunder ice cooling (internal temperature 4° C.), the precipitated solidwas collected by filtration, and dried under reduced pressure, to obtainbenzenesulfonate of compound A in white (301 mg).

¹H-NMR (500 MHz,DMSO-d₆):

δ 4.08 (s,2H), 4.49 (s,2H), 7.29-7.39 (m,7H), 7.59-7.61 (m,2H), 7.81(d,J=9.2 Hz,2H), 8.03 (d,J=7.6 Hz,1H), 8.14 (s,1H), 8.27 (d,J=5.5Hz,1H), 8.59 (dd,J=4.9,1.8 Hz,1H), 10.37 (bs,1H), 10.66 (s,1H)

PXRD:

TABLE 12 Peak Angle Angstrom 2θ° d = 4.4665 19.861 d = 4.3709 20.301 d =3.8438 23.120 d = 2.3398 38.441

Example 18 Production Method 17 of Benzenesulfonate of Compound A (αcrystal) (Ethanol/DMSO, Leaving Still at Room Temperature)

To benzenesulfonate of compound A (4.0 g) was added dimethylsulfoxide(9.0 mL), and then stirred at room temperature (internal temperature 25°C.) for 6 minutes. After confirming dissolution, ethanol (45 mL) wasadded. After stirring at room temperature for 1.0 hour, the precipitatedsolid was collected by filtration, and dried under reduced pressure, toobtain benzenesulfonate of compound A in white (3.3 g).

¹H-NMR (500 MHz,DMSO-d₆):

δ 4.08 (s,2H), 4.49 (s,2H), 7.30-7.39 (m,7H), 7.59-7.61 (m,2H), 7.81(d,J=9.2 Hz,2H), 8.03 (dd,J=7.6,1.5 Hz,1H), 8.14 (s,1H), 8.27 (d,J=5.8Hz,1H), 8.59 (dd,J=4.9,1.5 Hz,1H), 10.40 (bs,1H), 10.67 (s,1H)

PXRD:

TABLE 13 Peak Angle Angstrom 2θ° d = 4.4705 19.843 d = 4.3709 20.300 d =3.8499 23.083 d = 2.3399 38.440

Example 19 Production Method of Benzenesulfonate of Compound A (βCrystal)

To compound A (507 mg) was added tetrahydrofuran (5.0 mL) and stirred atroom temperature. After confirming dissolution, benzenesulfonic acidmonohydrate (202 mg) was added at the same temperature, and stirred foranother 1.5 hours. The precipitated solid was collected by filtration,and dried under reduced pressure, to obtain benzenesulfonate of compoundA in white (591 mg).

¹H-NMR (500 MHz,DMSO-d₆):

δ 4.05 (s,2H), 4.47 (s,2H), 7.27-7.38 (m,7H), 7.58-7.60 (m,2H), 7.80(d,J=9.2 Hz,2H), 8.02 (dd,J=7.6,1.8 Hz,1H), 8.16 (s,1H), 8.24 (d,J=5.5Hz,1H), 8.59 (dd,J=4.9,1.5 Hz,1H), 10.05 (bs,1H), 10.66 (s,1H)

PXRD:

TABLE 14 Peak Angle Angstrom 2θ° d = 8.0767 10.945 d = 6.8137 12.982 d =4.2876 20.699 d = 4.1260 21.519 d = 3.9623 22.420

TGA:

Endothermic peak: 205.5° C.

In the analysis of PXRD in the foregoing [Production examples], copperradiation (40 kV/40 mA) was used as a radiation source, and measurementwas conducted with the following scanning parameters: scan axis: 2θ/θ,range: 2.500-40.000°, scanning mode: continuous, sampling width: 0.020°,and scan speed: 4.000°/min.

As to the TGA analysis, about 5 mg of a sample was used, and each samplewas scanned at 25.0 to 300.0° C. at a rate of 10.00° C/minute. At thistime, a nitrogen gas was made to constantly flow in a crucible at a flowrate of 150.0 mL/minute.

<Storage Stability Tests for Benzenesulfonate, Methanesulfonate andP-Toluenesulfonate of Compound A (1-week Preliminary Stability Test)>

(Test Method)

For benzenesulfonate, methanesulfonate and p-toluenesulfonate ofcompound A, after storing under the conditions of 40° C. 75% RH, 60° C.or light (1000 lux/hr), the content of each salt of compound A wasmeasured by HPLC. The percentage of change, relative to the contentbefore storage of 100%, was calculated.

(Test Result)

TABLE 15 Benzene- Methane- p-toluene- Storage condition sulfonatesulfonate sulfonate 40° C. 75% RH/1 week 100.0% 99.8% 92.3% 60° C./1week 100.0% 99.9% 99.3% 1000 lux/hr, 1 week 100.0% 99.1% 99.8%<Side Effect Verification Test (Rat 1-week Repeated Oral AdministrationToxicity Test of Compound A (free body) and Rat 4-week Repeated OralAdministration Toxicity Test of Benzenesulfonate of Compound A)>

-   1) Rat 1-week repeated oral administration toxicity test of compound    A (free body)    (Test and Observation Method)-   i) To Crl:CD (SD) rat was orally administered compound A (10 mL/kg    (body weight), 30 mL/kg (body weight)) suspended in a 1%    methylcellulose liquid once a day for 7 days.-   ii) After completion of the administration, the rat was    exsanguinated to death under ether anesthesia, then the stomach was    removed, fixed in a 10% neutral buffered formalin aqueous solution,    and then stained with hematoxylin-eosin to prepare a specimen, and    the change in the stomach was observed histopathologically.-   2) Rat 4-week repeated oral administration toxicity test of    benzenesulfonate of compound A    (Test and Observation Method)-   i) To Crl:CD (SD) rat was orally administered benzenesulfonate of    compound A (10 mL/kg (body weight), 30 mL/kg (body weight))    suspended in a 1% methylcellulose liquid once a day for 4 weeks.-   ii) After completion of the administration, the rat was    exsanguinated to death under ether anesthesia, then the stomach was    removed, fixed in a 10% neutral buffered formalin aqueous solution,    and then stained with hematoxylin-eosin to prepare a specimen, and    the change in the stomach was observed histopathologically.    (Test Result)

In contrast to compound A for which mineral deposition in the stomachwas observed after 1-week repeated oral administration, mineraldeposition in the stomach was not observed even after 4-week repeatedoral administration for benzenesulfonate of compound A.

Formulation Examples

Representative formulation examples of the present compound will beshown below.

Prescription Example 1 Tablet (in 100 mg)

Present compound 1 mg Lactose 66.4 mg Corn starch 20 mg Carboxymethylcellulose calcium 6 mg Hydroxypropyl cellulose 4 mg Magnesium stearate0.6 mg

By appropriately varying the kind and/or the amount of the presentcompound and/or the additives, a desired tablet can be obtained. Such atablet can be coated with a coating agent (for example, normal coatingagents such as hypromellose, macrogol and silicone resin) to obtain anintended coated tablet.

Prescription Example 2 Capsule (in 150 mg)

Present compound  5 mg Lactose 145 mg

By appropriately varying the mixing ratio of the present compound andlactose, a desired capsule can be obtained.

Prescription Example 3 Eye Drop (in 100 mL)

Present compound 100 mg Sodium chloride 900 mg Polysorbate 80 200 mgBenzalkonium chloride  5 mg Sodium hydroxide quantum libet Hydrochloricacid quantum libet Sterilized purified water quantum libet

By appropriately varying the kind and/or the amount of the presentcompound and/or the additives, a desired eye drop can be obtained.

INDUSTRIAL APPLICABILITY

The present invention provides benzenesulfonate of compound A that ishighly safe, excellent in storage stability, and useful as apharmaceutical, a crystal of the same, a crystal polymorph thereof, andproduction methods thereof The present invention also provides apharmaceutical containing at least one selected from the groupconsisting of benzenesulfonate of compound A, a crystal of the same, anda crystal polymorph thereof

The invention claimed is:
 1. A crystal of benzenesulfonate of2-[[[2-[(hydroxyacetyl)amino]-4-pyridinyl]methyl]thio]-N-[4-(trifluoromethoxy)phenyl]-3-pyridiriecarboxamide having characteristic peaks at 4.4angstroms, 3,8 angstroms and 2,3 angstroms as a d value of powder X-raydiffraction pattern.
 2. A crystal of benzenesulfonate of2-[[[2-((hydroxyacetyl)amino]-4-pyridinyl]methyl]thio]-N[4-(trifluoromethoxy)phenyl]-3-pyridinecarboxamide having characteristic peaks at 8.1angstroms, 6.8 angstroms, 4.1 angstroms and 4.0 angstroms as a d valueof powder X-ray diffraction pattern.